Parathyroid hormone (PTH) is a peptide hormone with a major role in calcium metabolism. In addition, a daily recombinant form of PTH (1-34, teriparatide) is the only FDA-approved anabolic osteoporosis treatment. To date, we do not fully understand the detailed cellular and molecular mechanism of teriparatide's anabolic effect. PTH receptors are expressed in osteocytes, and PTH signaling in osteocytes is likely to be vital for the ability of teriparatide to stimulate net bone production. Sclerostin is an osteocyte-derived inhibitor of bone formation by osteoblasts whose expression is down-regulated by PTH. Sclerostin is a novel drug target for osteoporosis, and sclerostin inhibition by PTH is likely to b an important mechanism underlying the teriparatide treatment effect. This proposal aims to study the molecular mechanisms whereby PTH signaling in osteocytes leads to sclerostin down-regulation. Our hypothesis is that class IIa histone deacetylase (HDAC) proteins play an essential role in the pathway between the PTH receptor and sclerostin inhibition. We plan to study the role of class IIa HDACs in this pathway using a combination of in vitro and in vivo approaches. First, levels of class IIa HDACs will be manipulated using shRNA-mediated gene silencing in a novel osteocytes cell line which displays robust PTH-dependent sclerostin down-regulation. Next, detailed mechanistic studies will be performed to understand how class IIa HDACs function in the pathway leading from PTH to sclerostin down-regulation. Finally, mice lacking class IIa HDACs in osteocytes will be studied to determine if class IIa HDACs are required for PTH to reduce sclerostin levels in vivo. These studies will provide key data regarding the signaling pathways in osteocytes underlying teriparatide's osteoanabolic effect. In addition, an improved understanding of these pathways may lead to the development of novel therapies for osteoporosis.